Medicine: Another Piece of the Alzheimer's Puzzle

In 1907, German neurologist Alois Alzheimer described the two primary pathological characteristics--neurofibrillary tangles and amyloid plaques
--that have since defined the dementing disease of aging that today bears his name. Now, for the first time since then, researchers at the University of
Pennsylvania Medical Center have identified a major new pathological feature of Alzheimer's disease, equally abundant and widespread in the brains
of patients and as specific to the disease as the long-known tangles and plaques.

The newly discovered pathology--a plaque-like lesion involving a previously unidentified protein--appears to constitute as much as a quarter to
a third of the volume of affected gray matter tissue in Alzheimer's disease brains. Additionally, it is rare or absent in other neuro-degenerative diseases.
As such, it represents an important new clue concerning the origins and course of Alzheimer's disease and a likely target for therapeutic interventions
to slow or halt this baffling and devastating disease.

"This is a spectacular lesion, never before seen, that tracks closely with the disease state--more specifically than tangles and perhaps more
specifically than amyloid plaques," said Dr. John Q. Trojanowski, the professor of pathology and laboratory medicine and director of the Alzheimer's
Disease Center at Penn who is senior author on the study report, which appears in the July issue of the
American Journal of Pathology. "It occupies
as much of the Alz-heimer's brain as amyloid plaques do. As a result, we have every reason to suspect that this pathology will be found to play a crucial
role in the development and progression of Alzheimer's disease."

"I find this discovery very exciting because it introduces a new element into the study of this complex disease process," adds Dr. Marcelle Morrison
-Bogorad, associate director of the Neuroscience and Neuropsychology of Aging program at the National Institute on Aging. "These plaque-like
structures have never before been identified in Alzheimer's brains. The new and mysterious protein found in these structures may prove very useful
in future research endeavors into the causes and evolution of a dreadful disease."

Dr. Zaven Khachaturian, director of the Alzheimer's Association Ronald and Nancy Reagan Research Institute also called it a significant finding.
"If confirmed, this may become a central issue in our understanding of Alzheimer's disease," he said. "This discovery may open fresh avenues for
investigating the cause or causes of Alzheimer's, give us a new diagnostic marker, and provide new targets for treatments."

A question likely to be asked is how such a pervasive pathology in an intensely studied disease could go undetected for so many years.

"The staining and chemical dye methods that have been used in the past to label Alzheimer's disease pathologies--primarily silver and thioflavin
staining--do not pick up this lesion," notes Dr. Virginia M.-Y. Lee, a professor of pathology and laboratory medicine who collaborated closely on the
research and is co-author of the article. "A new series of antibodies we created to explore elements of the neurofibrillary tangles, however, did."

Drs. Trojanowski, Lee, and colleagues generated four monoclonal antibodies from immunogens found in the tangles, hoping to be able to use the
antibodies to tag and learn more about the proteins that make up those structures. To their surprise, the antibodies did not recognize proteins in their
intended targets but, instead, revealed the extensive new lesion. Further analysis with one of the four antibodies--called AMY117--showed the plaque
-like structures to consist of a novel protein with a molecular weight of 100 kilodaltons that never colocalized with the previously known amyloid
plaques.

In current experiments, the researchers are hoping to be able to clone and sequence the gene that codes for the new protein. The lead author on the
study is Dr. Marie Luise Schmidt, senior research investigator, and other co-authors are Dr. Mark Forman of HUP and Ting-Shan Chiu of the technical
staff. Funding support was provided by the National Institute on Aging.